Asthma is a major public health problem in the United States affecting over 23 million Americans and costing US society $56 billion annually. Despite advances in treatment of asthma, there remains significant unmet therapeutic need, and large subgroups of asthmatics have poor asthma control despite current asthma treatment. Consequently, asthma exacerbations, often precipitated by viral airway infections, continue to result in 2 million emergency room visits a year in the US. The largest molecular phenotype of asthma Is one that is driven by TH2 inflammation and characterized by eosinophilic inflammation, and the project proposed here focuses on clinical studies ofthe mechanisms of TH2 inflammation, including how TH2 inflammation can be amplified during viral-Induced asthma exacerbations. A key rationale for the research aims we propose here Is the increasing recognition that signals from the epithelium to innate cells contribute Importantly to mechanisms of airway Inflammation. The signals we propose to focus on are IL-33 and Its receptor (ST2) and the interactions of IL-33 with ST2-bearing innate helper type 2 cells (iH2) cells, a novel lineage-negative population of cells that secrete IL-5 and IL-13 In response to IL-33. iH2 cells represent a novel cellular source of TH2 cytokines and a cell type that this PPG hypothesizes to have a central role In mechanisms of airway TH2 Inflammation in asthma. Coincident with recent discoveries about iH2 cells has been publication of GWAS studies showing that genetic polymorphisms in IL-33 and ST2 are among a relatively short list of genes consistently associated with asthma. All of these new data suggest new ways by which airway epithelial cells can initiate and amplify type 2 Immune responses In the airway, and we will explore these new possibilities in three aims: Aim 1 will determine the role of IH2 cells as cellular mediators of TH2 inflammation. Aim 2 will determine how IL-33 regulates airway TH2 Inflammation during asthma exacerbations. Aim 3 will determine how genetic variants in ST2 Influence airway TH2 inflammation. In tackling these alms we will advance knowledge for mechanisms of airway TH2 Inflammation in asthma. RELEVANCE (See instructions): Asthma is a common disease and a major public health problem. It cannot be cured and many patients are not optimally controlled using current treatments. Our project will help advance understanding of basic mechanisms of airway Inflammation in patients with asthma and help Identify new approaches for treatment.